This project is focused on the clinical study of patients with AIDS-related malignancies. Much of the work is focused on tumors associated with Kaposis sarcoma-associated herpesvirus (KSHV), also called human herpesvirus-8 (HHV-8). This virus is the cause of Kaposis sarcoma (KS), primary effusion lymphoma (PEL) and multicentric Castlemans disease (MCD). We are also studying antibody to VEGF (bevacizumab) as a therapeutic agent in KS as well as BAY 43-9007 (sorafineb). Bevacizumab was shown in an initial tril to have clinical activity in about 30% of patients. Sorafineb is of interest because it can downregulate several receptors for VEGF. We have also initiated a trial of bevacizumab in combination with liposomal doxorubicin in patients with severe KS. Most recently, we initiated a trial of pomalidomide in KS. We have initiated a clinical trial to study the natural history of MCD and to explore the treatment of MCD using a combination of AZT and valganciclovir, a pro-drug of ganciclovir as well as several other approaches (including liposomal doxorubicin and rituxuimab). Initial results show that AZT plus ganaiclovir has substantial activity, although relapses are common when used alone. In addition, we are studying other patients with KSHV infection to assess factors that may be linked to malignancy. We are exploring methotrexate-based therapy for primary central nervous system lymphoma (PCNSL). We are also studying infusional chemotherapy as therapy for AIDS-associated lymphoma in collaboration with the Metabolism Branch. We have identified a group of patients with a new KSHV-related syndrome, called KSHV inflammatory cytokine syndrome (KICS), and have just opened a protocol to study this new disease. Finally, as part of this effort, we are collaborating with a number of other investigators to conduct translational studies related to HIV, AIDS-malignancies, and also xenotropic murine leukemia-virus related virus (XMRV).